2-amino-3-carbamido-quinoxaline-di-n-oxides and their production

ABSTRACT

2-Amino-3-carbamido-quinoxaline-di-N-oxides of the formula   ARE PRODUCED BY HYDROLISING THE CORRESPONDING 2-AMINO-3-CYANOQUINOXALINE-DI-N-oxides of the formula   IN AN ACIDIC SOLUTION WHEREIN R is hydrogen, halogen, lower alkyl or lower alkoxy. The compounds are useful in treatment of infections from grampositive and gramnegative bacteria and are administered in the general range of 25 mg./kg. orally or parenterally.

United States Patent Florin Seng Cologne;

Kurt Ley, Odenthal; Karl Georg Metzger, Wuppertal-Elberleld; DieterFritsche, Wuppertal-Vohwinkel, all of Germany [72] inventors [2]] App].No. 742,168

[22] Filed July 3, 1968 [45] Patented Sept. 28, 1971 [73] AssigneeFarbenlabriken Bayer Aktiengesellschalt Leverkusen, Germany [32]Priority July 26, 1967 [3 3 Germany [54] Z-AMINO-S-CARBAMIDO-QUlNOXALlNE-Dl-N- OXIDES AND THEIR PRODUCTION PrimaryExaminer-Nicholas S. Rizzo Attorney-J acobs & Jacobs ABSTRACT:2-Amino-3-carbamido-quinoxaline-di-Noxidcs of the formula are producedby h drolisi n the corresponding 2-amino-3- F "JPHBEEESlEIQXL@919? fe qlin an acidic solution wherein R is hydrogen, halogen, lower alkyl orlower alkoxy. The compounds are useful in treatment of infections fromgrampositive and gramnegative bacteria and are administered in thegeneral range of 25 mgJkg. orally or parenterally.

2-# MINO-3-CARBAMIDO-QUINOXALINE-DI-N-OXIDES AND THEIR PRODUCTION lowingformulae:

is hydrolyzed in acidic solution.

Taking 2-amino-3-carbonamido-quinoxaline-di-N-oxide as an example, thereaction is illustrated by the following cqua The hydrolysis isexpediently carried out by dissolving the 2-amino-3-cyano-quinoxaline-di-N-oxides in sulfuric acid at aconcentration of 80-100 percent, preferably approximately 96 percent,the remainder being water, and subsequently stirring at hydrolysistemperature. This temperature is generally 2580 C, preferably 50-70 C.After neutralization,

preferably with an aqueous ammonia solution or with the aqueous solutionof an oxide, hydroxide, carbonate or bicarbonate of an alkali metal oralkaline earth metal, particularly sodium, potassium or magnesium, the2-amino-3-cyano-quinoXaline-di-N-oxides are obtained as crystallinecompounds.

The new 2-amino-3-cyano-quinoxaline-di-N-oxides required as startingmaterials are obtainable, according to our own previous proposal, byreacting benzofuroxans with malonic acid dinitrile in the presence of acatalytic amount of an amine.

The process of the invention is illustrated by the followingnonlimitative examples.

Example 1 Preparation of 2-amino-3-carbonamid0-quinoxaline-di-N- oxide(1; R=H).

250 g. (1.25 mole) of Z-amino-3-cyano-quinoxaline-di-N- oxide aredissolved in a mixture of 1,000 ml. of 96 percent sulfuric acid and 40g. of water and stirred at 60 C. for 5 hours. The solution issubsequently poured on to 1.5 kg. of ice and neutralized with 2,650 ml.of 33 percent ammonia. 250 g. (92.6 percent of theory), of2-amino-3carbonamido-quinoxaline-di-N-oxide are obtained in the form ofred crystals which decompose, after recrystallization from dimethylformamide, at 242-243 C.

The 2-amino-3-cyano-quinoxaline-di-N-oxide used as starting compound isobtained as follows: 13.6 g. (0.1 mole) of benzofuroxan are suspended in150 ml. of ethanol and mixed with 6.6 g. (0.1 mole) of malonic aciddinitrile. 8.5 g. (0.1 mole) of piperidine are slowly added dropwise.The suspended benzofuroxan dissolves and the temperature of the reactionmixture rises to 3070 C., depending on the speed of the dropwiseaddition. After 3 hours, the mixture is cooled to about +5 C. and afterfiltering off with suction, 13 g. (64.3 percent of theory) of2-amino-3-cyano-quinoxaline-di-N- oxide are obtained in the form of redcrystals; m.p. 22l-1 13 C. (from dimethyl formamide). When the processis carried out in dimethyl formamide, the yield rises to 86 percent oftheory.

tion:

Example 2 o o e i T o /N\ ON N\ 6 NH H O H S O4 2 The compounds ll-IVlisted in the Table were prepared ac- NH 2 cording to the process ofexample 1 using 7-methyl, 7-chloro- N z N or 7-methoxy-2-amino-3-cyano-quinoxaline-di-N-oxide g l T respectively as the startingmaterial, which is obtained as O- 'H (3) being obvious for example 1:

TOIHIHI'U ture of decompo- Ylvlrl, Compound Number Color sitlon, (Y.percent II 0 Yellow-red. 226-228 91. T

Temperature of dneompo- Yield, Compound Number Color sltlon, 0. percent.

111 t) l )ulk-red 240 93. 4

T I N -N l l i (I l N ll N y l .[1

1V .do 246-247 92. 4

The bactericidal activity of the compounds according to the presentinvention has been proven both in vitro tests exhibiting goodantibacterial effect and in vivo tests on animals, The compounds of thepresent invention may be administered orally or parenterally. The mostadvantageous dosage range has been found to be from about mg. to about500 mg. and more particularly dosage ranges from about 25 mg./kg. toabout 150 mg./kg. per day have exhibited beneficial and effectiveresults.

It is, however, to be appreciated that in administering compounds of thepresent invention as is the case with a therapeutic substance a varietyof factors must be taken into consideration in determining the dosage tobe administered in the given case. These factors include the body weightof the patient receiving the compound, the severity of the condition tobe treated, the postmedicai history and the current state of health.Depending upon these and other factors it is possible that dosage rangeslower than or higher than the above indicated ranges could be utilizedeffectively. in the case where fairly large amounts are to beadministered it is generally recognized to be advisable to distributethe total daily dose by administering several individual doses duringthe course of a day.

The compounds of the present case can be administered either as such orin combination with pharmaceutically acceptable, nontoxic carriers.

Suitable forms of administration in combination with various inertcarriers are tablets, capsules, powders, sprays, aqueous suspensions,injectable solutions (which may be contained in ampuls), elixirs, syrupsand the like. Such carriers include solid extenders or fillers, asterile aqueous medium as well as various nontoxic organic solvents andthe like. Obviously, the tablets and the like intended for oraladministration can be provided with saccharine or similar additives. Thetherapeutically active compound should be present in the aforesaid casein a concentration of about 0.5 to 90 percent by weight of the totalmixture, that is in amounts which suffice to achieve the dosagementioned above.

in case of oral application, the tablets may of course also containadditives such as sodium citrate, calcium carbonate and dicalciumphosphate, together with various admixture such as starch, preferablypotato starch and the like, and binders, such as polyvinyl-pyrrolidonc,gelatin and the like. Furthermore. lubricants such as magnesiumstearate, sodium sulfate and talc can be added for producing tablets. inthe case of aqueous suspensions and/or elixirs intended for oraladministration, the active compound can be used with various tasteimprovcrs, dyestuffs, emulsifiers and/or dispersing agents, togetherwith diluents, such as water, ethanol, propylene glycol, glycerine andsimilar compounds or combinations.

In the case of parenteral administration, there may be used solutions orsuspensions of the active compounds in sesame oil or peanut oil or inaqueous propylene glycol or N,N-dimethyl formamide. When required, suchsolutions or suspensions should first be rendered isotonic by theaddition of the neces sary amount of salt or glucose. Solutions orsuspensions of this type are mainly suitable for intramuscular andintraperitoneal injections.

The actual formulation of such forms of administration are per se known.

The effectiveness of the compounds of the present invention is moreclearly appreciated by the following experiments or compoundsrepresentative of those embraced by formula l.

in animal tests on white mice, the animals were infectedintraperitoneally and treated subcutaneously or orally as fol lows:

l. Single doses of 25, 50, 200 and 500 mg./kg. prior to infection.

2. Two doses of i5 and 20 mg./kg., respectively, 2 hours before and 3hours after the infection.

These dosages were well tolerated.

Depending on the compound the acute toxicity range for rats and mice isbetween 150 and about 1,000 mg./kg. in the case of a single oraladministration. The use of the new compounds against mycoplasmainfections is also envisaged. l. Animal tests on white mice:

2. inhibition values in vitro:

Minimum inhibition concentrations in ,ugJml. nutrient 0! compoundBacterium I (R=H) I! (R=CH3) lli (R=Cl) E. coll. 50 150 Proteus up 50100 100 Klebsielle s 60 100 Staph. aureus- 60 100 100 Strept. pyogenes150 100 100 The 2-smino-3carbonamidc-di-N-oxides show furthermore (samegeneral dosage range as disclosed) activity against amoeba andflagcllata (E. histolytica, Trichomonas vaginalis,

Lamblia muris) both in invitro tests and in vivo tests on animals (mice,rats, golden-hamsters). compounds I, [I and Ill are respectively thoseof the general formula 1, wherein R is hydrogen (1), methyl (ll) orchlorine ([1]).

When the compounds of the present invention are utilized in the form ofpharmaceutical compositions these must be dispensed in unit dosage form.The individual preparations can therefore be made up each containing aunit dose, 2, 3 or 4 unit doses, a half, a third or a fourth ofa unitdose or the like as desired.

We claim:

1. 2-Amino-3-carbonamido-di-N-oxides of the formula:

0 13 ll o-om in which R is hydrogen, halogen, lower alkyl or loweralkoxy.

2. A compound according to claim 1 in which R is hydrogen, methyl,methoxy or chlorine.

3. The compound according to claim 1, wherein R is methyl of the formulaCCNH:

/ N NE CH 1' 4. The compound according to claim 1, wherein R is chloroof the formula W-conm NH N 01 t l 5. The compound according to claim 1,wherein R is methoxy of the formula C 150 l I 6. The compound accordingto claim 1, wherein R is hydrogen of the formula 0 13 15 CONH,

7. 2-Amino-3-carbamido-quinoxaline-di-N-oxide of the formula -NH, -c-NH,R 2 R 22 r T i J,

0 i l CNH R N NH wherein R is hydrogen, halogen, lower alkyl or loweralkoxy.

8. 2 -Amino-3-cyano-di-N-oxide of the formula g N CN \N/ NH in which Ris hydrogen, halogen, lower alkyl or lower alkoxy.

Inventor(s) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,609,151 Dated September 28, 1971 Florin Seng, Kurt Ley, Karl Georg Metzgerand Dieter Fritsche Patent No.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

. I In claim 1, the structural formula reading:

1 o l-0H, E 9 a a I should read: R 1 x J, L 0...

. all

In claim 3, the structural formula reading:

cam, Q N Na should read: Q a". on

' I ca 5/ NH In claim 7, the structural formula appearing at line 35,reading:

0 T O Law. 9 o a should read: a

N8 l N 6!! 5 N Signed and sealed this 4th day of April 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK v." Attesting OfficerCommissioner of Patents

2. A compound according to claim 1 in which R is hydrogen, methyl,methoxy or chlorine.
 3. The compound according to claim 1, wherein R ismethyl of the formula
 4. The compound according to claim 1, wherein R ischloro of the formula
 5. The compound according to claim 1, wherein R ismethoxy of the formula
 6. The compound according to claim 1, wherein Ris hydrogen of the formula
 7. 2-Amino-3-carbamido-quinoxaline-di-N-oxideof the formula
 8. 2-Amino-3-cyano-di-N-oxide of the formula